Lactate induces metabolic and epigenetic reprogramming of pro-inflammatory Th17 cells.
Aleksandra Lopez KrolHannah P NehringFelix F KrauseAnne WempeHartmann RaiferAndrea NistThorsten StieweWilhelm BertramsBernd SchmeckMaik LuuHanna LeisterHo-Ryun ChungUta-Maria BauerTill AdhikaryAlexander VisekrunaPublished in: EMBO reports (2022)
Increased lactate levels in the tissue microenvironment are a well-known feature of chronic inflammation. However, the role of lactate in regulating T cell function remains controversial. Here, we demonstrate that extracellular lactate predominantly induces deregulation of the Th17-specific gene expression program by modulating the metabolic and epigenetic status of Th17 cells. Following lactate treatment, Th17 cells significantly reduced their IL-17A production and upregulated Foxp3 expression through ROS-driven IL-2 secretion. Moreover, we observed increased levels of genome-wide histone H3K18 lactylation, a recently described marker for active chromatin in macrophages, in lactate-treated Th17 cells. In addition, we show that high lactate concentrations suppress Th17 pathogenicity during intestinal inflammation in mice. These results indicate that lactate is capable of reprogramming pro-inflammatory T cell phenotypes into regulatory T cells.
Keyphrases
- induced apoptosis
- gene expression
- regulatory t cells
- cell cycle arrest
- dna methylation
- genome wide
- oxidative stress
- cell death
- dna damage
- stem cells
- machine learning
- endoplasmic reticulum stress
- type diabetes
- dendritic cells
- cystic fibrosis
- adipose tissue
- transcription factor
- deep learning
- reactive oxygen species
- newly diagnosed
- candida albicans
- biofilm formation
- high fat diet induced